Phamacologically active 5-carboxy-2-(5-tetrazolyl) pyridines

Abstract

Compounds of the formula I ##STR1## wherein the groups A, R 1 , R 2 and R 3 are as defined in the specification, exhibit valuable pharmacological properties, especially as antifibrotic agents. They are prepared by methods known per se.

We claim: 
     
       1. A member selected from the group consisting of (a) a compound of formula ##STR6## wherein A represents 5-tetrazolyl which is unsubstituted or is substituted in the 2-position by a member selected from the group consisting of (1) C 1  -C 20  alkyl, (2) amino-lower alkyl, (3) mono-lower alkylamino-lower alkyl, (4) di-lower alkylamino-lower alkyl, (5) carboxy-lower alkyl, (6) lower alkoxycarbonyl-lower alkyl, (7) aryl-lower alkyl, (8) hydroxy-lower alkyl, (9) lower alkanoyloxy-lower alkyl, (10) lower alkoxy-lower alkyl, (11) hydroxy-lower alkoxymethyl, (12) lower alkanoyloxy-lower alkoxymethyl, (13) lower alkoxy-lower alkoxymethyl, (14) 1-alkoxycarbonyl-1-lower alkoxy-methyl, (15) 3-phthalidyl, (16) lower alkyl-3-phthalidyl, (17) lower alkoxy-3-phthalidyl, (18) halogen-3-phthalidyl, (19) lower alkoxycarbonyloxy-lower alkyl and (20) lower alkanoyl; R 1  represents carboxy or a pharmaceutically acceptable ester group thereof;   R 2  represents hydrogen or a member selected from the group consisting of lower alkyl, cycloalkyl, aryl-lower alkyl, heteroaryl-lower alkyl and aryl each of which members can be unsubstituted or substituted; and   R 3  represents hydrogen;     (b) a tautomer thereof and (c) a pharmaceutically acceptable salt thereof.   
     
     
       2. A compound according to claim 1, wherein   R 2  represents hydrogen or a member selected from the group consisting of lower alkyl, cycloalkyl, aryl-lower alkyl, heteroaryl-lower alkyl and aryl each of which members can be unsubstituted or substituted by amino, lower alkylamino, di-lower alkylamino, N-piperidino, N-morpholino, N-thiomorpholino, N-piperazino, 4-(lower alkyl or lower alkanoyl)-N-piperazino, lower alkoxy, C 3  -C 14  -alkoxy wherein the alkyl chain is interrupted by 1 to 5 oxy groups, or C 3  -C 14  -alkylamino wherein the alkyl chain is interrupted by 1 to 5 oxy and/or imino groups; and   R 3  represents hydrogen.   
     
     
       3. A compound according to claim 1, wherein   A represents 5-tetrazolyl, 2-lower alkanoyl-5-tetrazolyl or 2-(1-lower alkoxycarbonyl-1-lower alkoxy-methyl)-5-tetrazolyl;   R 1  represents carboxy, C 1  -C 20  -alkoxycarbonyl or 1-lower alkoxycarbonyl-1-lower alkoxy-methoxycarbonyl;   R 2  represents hydrogen, lower alkyl, C 5  -C 7  -cycloalkyl, phenyl-lower alkyl or phenyl, wherein in the latter two radicals, phenyl is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy and/or halogen; and R 3  represents hydrogen; a tautomer of said compound or a pharmaceutically acceptable salt of said compound.   
     
     
       4. A compound according to claim 1, wherein   A represents 5-tetrazolyl, 2-lower alkanoyl-5-tetrazolyl or 2-(1-lower alkoxycarbonyl-1-lower alkoxy-methyl)-5-tetrazolyl;   R 1  represents carboxy, C 1  -C 20  -alkoxycarbonyl or 1-lower alkoxycarbonyl-1-lower alkoxy-methoxycarbonyl;   R 2  represents hydrogen, lower alkyl, C 5  -C 7  -cycloalkyl or phenyl; and   R 3  represents hydrogen; a tautomer of said compound or a pharmaceutically acceptable salt of said compound.     
     
     
       5. A compound according to claim 1, wherein R 2  and R 3  represent hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
       6. A compound according to claim 1, wherein A represents 5-tetrazolyl, R 1  represents carboxy or lower alkoxycarbonyl, R 2  is hydrogen, lower alkyl, cycloalkyl, phenyl-lower alkyl or phenyl, wherein in the latter two radicals, phenyl is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy and/or halogen, and R 3  represents hydrogen; a tautomer of said compound or a pharmaceutically acceptable salt of said compound. 
     
     
       7. A compound according to claim 1, wherein A represents 5-tetrazolyl, R 1  is carboxy or lower alkoxycarbonyl, R 2  is hydrogen or lower alkyl and R 3  represents hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
       8. A compound according to claim 1, said compound being 5-carboxy-2-(5-tetrazolyl)-pyridine. 
     
     
       9. A compound according to claim 1, said compound being hexadecyl 2-(5-tetrazolyl)pyridine-5-carboxylate. 
     
     
       10. A pharmaceutical composition comprising an amount of a compound, a tautomer or a salt according to claim 1 effective for the treatment of diseases responsive to collagen proline-4-hydroxylase inhibition in mammals together with at least one pharmaceutically acceptable carrier. 
     
     
       11. A method of treating diseases responsive to collagen proline-4-hydroxylase inhibition in mammals comprising the administration to a mammal in need thereof of a therapeutically effective amount of a compound, a tautomer or salt according to claim 1. 
     
     
       12. A method of decreasing collagen synthesis in a mammal comprising the administration to said mammal of an effective amount of a compound, a tautomer or salt according to claim 1.